Positron emission tomography (PET) will be used to investigate the capacity to alter neurochemical function in response to acute neuroleptic- induced receptor blockade in chronic schizophrenia. A neuroleptic challenge paradigm will be used to test the hypothesis that the capacity to alter neurochemical function in response to acute, neuroleptic-induced receptor blockade is associated with the capacity to produce a therapeutic response to long-term neuroleptic treatment. PET and 18/F-fluoro-2- deoxyglucose (FDG) will be used in a repeated measures design to examine regional changes in glucose metabolism following administration of a single pharmacological challenge dose of the neuroleptic drug haloperidol sufficient to induce receptor blockade. By comparing the metabolic response to this challenge in clinically well-characterized treatment responsive and treatment resistant chronic schizophrenics, we will address our central hypothesis. PET and the muscarinic cholinergic ligand 11/C-benztropine (11/C-BZ) will also be used to measure regional changes in muscarinic activity following administration of the haloperidol challenge in order to characterize the effect of a dopamine-blocking neuroleptic challenge on the separate, but functionally-related muscarinic cholinergic system. By comparing the muscarinic response in treatment responsive and resistant schizophrenics, one aspect of our central hypothesis can be tested: that the capacity to alter neurochemical response to receptor blockade in a separate but functionally related neurotransmitter system is associated with the capacity to produce a therapeutic response to long-term neuroleptic treatment. By accomplishing these aims we will have defined a neurochemical measure that may predict drug treatment response in chronic schizophrenia. Such a measure may provide a neurochemical basis for interpreting treatment response, for clinical sub-typing and for developing new treatment strategies.